This invention relates generally to magnetic resonance imaging (MRI), and more particularly the invention relates to the use of MRI in tracking magnetically labeled cells or objects in the presence of magnetic field inhomogeneity using positive contrast.
Magnetic resonance imaging (MRI) requires placing an object to be imaged in a static magnetic field, exciting nuclear spins in the object within the magnetic field, and then detecting signals emitted by the excited spins as they process within the magnetic field. Through the use of magnetic gradient and phase encoding of the excited magnetization, detected signals can be spatially localized in three dimensions.
Contrast agents incorporating super-paramagnetic iron-oxide (SPIO) nanoparticles have shown much promise as a means to visualize labeled cells using MRI. The small size of the particles (<100 nm) facilitates transport across cell membranes, and the low toxicity allows for large iron loads without significant cell death (e.g., 25 pg/cell). Labeling can be performed by incubating cells of interest (e.g., embryonic stem cells) with the contrast agent in vitro, as well as a transfection agent, so that they can be monitored in vivo using MRI. Cells such as macrophages can be labeled in vivo by introducing the contrast agent into the bloodstream, with the uptake of the agent occurring by phagocytosis, which has been used to image atherosclerosis and other inflammatory processes. In more advanced schemes, SPIO-protein complexes that bind to the receptors on specific cells have been used.
Imaging in the presence of severe magnetic field inhomogeneities has been very challenging for magnetic resonance imaging applications. The ability to image directly adjacent to metallic implants for example, has been very limited due to image distortion and markedly shortened T2*. In addition, detection of super-paramagnetic iron oxide particles (SPIO) or similar paramagnetic particles has gained tremendous interest for molecular imaging applications. Specific applications include detecting of antibodies tagged with SPIO's or stem cells labeled with SPIO particles. The ability to detect these targeted contrast agents with high sensitivity and specificity would have enormous impact in the areas of molecular imaging, which target in vivo cellular and molecular processes for detection and assessment of important diseases such as cancer, cardiovascular diseases, Alzheimer's disease, to name a few. The ability to detect and track stem cells is critical in the evaluation of new stem cell therapies currently being developed for numerous applications in the body including diabetes, Parkinson's disease, Alzheimer's disease, spinal cord injury, myocardial cell regeneration, to name a few.
Detection of SPIO and other highly paramagnetic particles has relied primarily on signal decay mechanisms, ie: T2* decay. Although effective, this method is relatively insensitive and non-specific. Thus, the conspicuity of collections of these particles visualized with T2* sensitive pulse sequences is limited by the fact that signal is dark in a background of bright signal in the remainder of the image.
A new approach to SPIO detection has been recently described by Cunningham et al (See Cunningham et al, MRM 2005, 53:999-1005 and copending application Ser. No. 10/849,068, filed May 18, 2004). This method exploits the off-resonance environment created by these particles. It does so by using specially designed RF pulses that transmit RF power with relatively narrow bandwidths centered near at a dominant off-resonance frequency created by the SPIO. In this way, only spins in the direct vicinity of the SPIO particles are excited, while the remainder of the image where there are no particles, remains dark. This creates “positive contrast” and creates images with very high conspicuity bright regions that correspond to the location of the SPIO particles.